Establishing the Safety and Efficacy of Bedaquiline-Containing Regimen for the Treatment of Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

The risks and benefits of bedaquiline (BDQ) for treatment of drug-resistant tuberculosis (DR-TB) have not been firmly established. We aimed to assess the safety and efficacy of BDQ-containing regimens for the treatment of DR-TB as evidenced in available randomized controlled trials (RCTs). In this systematic review and meta-analysis, five databases (i.e., ClinicalTrials.gov, Cochrane CENTRAL, PubMed, ScienceDirect, and SinoMed) were searched. RCTs among DR-TB patients that had a control arm were eligible. The safety endpoints were all-cause mortality and serious adverse effects (SAEs). Efficacy outcomes were sputum culture conversion rate at 8–12 weeks and 24–26 weeks, treatment success, and time to culture conversion. A total of 476 records were screened; 18 met the eligibility criteria. The pooled analysis included 2520 participants (55.8% received BDQ-containing regimens, n = 1408). Pooled safety outcomes showed no significant reduction in all-cause mortality (relative risk [RR] [95%confidence interval (CI)] = 0.94 [0.41–2.20]) or SAEs (RR [95%CI] = 0.91 [0.67–1.23]) in the BDQ-regimen group. Pooled efficacy outcomes showed significantly superior culture conversion rates at 8–12 weeks (RR [95%CI] = 1.35 [1.10–1.65]) and 24–26 weeks (RR [95%CI] = 1.25 [1.15–1.36]), more treatment success (RR [95%CI] = 1.30 [1.17–1.44]), and a 17-day reduction in the time to culture conversion (standardized mean difference [SMD] [95%CI] = −17.46 [−34.82 to −0.11]) in the BDQ-regimen group (reference: non-BDQ regimen). Overall, BDQ regimens showed significant treatment effect against DR-TB but did not reduce mortality or SAEs.


Introduction
The burden of drug-resistant tuberculosis (DR-TB) is on the rise, reaching an estimated global prevalence of 11.6% [1].New resistance profiles of TB have continuously emerged since rifampin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) were defined by the World Health Organization (WHO) in 1994 [2].These changes in resistance profiles have rendered many TB medications ineffective, limiting the choice of effective drugs.The mortality rate is significantly higher among patients with MDR-TB (18%) and extensively drug-resistant TB (XDR-TB) (39%) compared to patients with drug-susceptible TB (DS-TB) (6%) [3].
Among the efforts to tackle this rising burden was the accelerated approval of bedaquiline (BDQ) (previously named TMC207 or diarylquinoline) for the treatment of DR-TB [4,5].In one of the earliest Phase 2 randomized controlled trials (RCTs), Diacon et al. reported a higher culture conversion rate and faster culture conversion rates among patients treated with BDQ compared to standard therapy [6].Similar findings were also reported by a multicenter large-scale cohort study of 29 countries as well as more recent RCTs [7][8][9].Nearly 70 countries worldwide have adopted the use of BDQ in their DR-TB therapeutic regimens [4].BDQ was a milestone in a new era of the fight against DR-TB.
To our knowledge, four meta-analyses are available on the safety and efficacy of BDQ-containing regimens for the treatment of DR-TB [10][11][12][13].These meta-analyses have methodological limitations.For example, they included both RCTs and observational studies.Observational studies, by design, cannot eliminate confounders and tend to have more biases; their inclusion may have increased the precision of the estimates but at the cost of inflated bias.Another limitation is that single-arm trials and trials with DS-TB patients were included in the analysis [11].These may explain the difference in their findings; Wang, Wu, and He [10] found a significant reduction in all-cause mortality with BDQcontaining therapy while Tong et al. [11] demonstrated insignificant mortality benefits.Similarly, pooled analysis of nonrandomized studies (NRS) by Tong et al. [11] demonstrated significant treatment success, contradicting Wang et al., which found an insignificant improvement in overall treatment success [10,11].
We have addressed these limitations and added a strength to this current systematic review and metaanalysis of BDQ by including (1) only RCT evidence, (2) RCTs with a control arm, (3) RCTs with all relevant outcomes, and (4) RCTs from China by searching a Chinese database.The objective of this meta-analysis was to determine the safety and efficacy of BDQ in the treatment of DR-TB.

Materials and Methods
2.1.Protocol and Registration.This systematic review and meta-analysis was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol.A comprehensive protocol was developed and submitted prospectively to the International Prospective Register of Systematic Reviews (PROSPERO) (identification number CRD42023426999).

Literature Search Strategy and Eligibility Criteria.
In order to identify all available RCTs, five databases were systematically explored: ClinicalTrials.gov,Cochrane CEN-TRAL, PubMed/MEDLINE, ScienceDirect, and SinoMed.The authors searched for all available studies published through mid-December 2023.Two different search strategies were implemented: using the Medical Subject Headings (MeSH) keywords and using text field search.The following predefined keywords were used to search and identify all relevant RCTs: "bedaquiline," "diarylquinoline," "drugresistant tuberculosis," "TMC207," and "TMC208."The keywords were translated into Chinese by author YS, a native Chinese speaker, to find the relevant records within the SinoMed scientific database.In addition, the references of the retrieved studies were comprehensively screened to identify and retrieve any potentially relevant RCTs.
This review included RCTs that fulfilled all the following criteria: (1) participants with DR-TB (including RR-, MDR-, pre-XDR-, and/or XDR-TB) in both the intervention and control arms, (2) an intervention arm with a BDQcontaining regimen, (3) a BDQ-free control arm, and (4) inclusion of safety and/or efficacy outcomes.The retrieved records were screened independently by three reviewers (MCJ, IS, and YS) to identify duplicates and fulfillment of eligibility criteria.Any discrepancy was solved among the three reviewers and the fourth coauthor.

Data Extraction.
Following a full-text review of the screened RCTs, data was extracted from the included studies.We used a predefined Excel sheet for data extraction that incorporated the following variables: the trial registry, name of the primary author, year of publication, country of the study, design of the RCT, blinding status, total sample size, sample size of each arm, sex distribution, median age, dosage and duration of BDQ administration, other antituberculous medications used for each arm, and the timing of the culture follow-up.The distribution of resistance profiles for each study was also recorded: RR-TB (i.e., TB that is resistant to rifampin), MDR-TB (i.e., TB that is resistant to both isoniazid and rifampin), pre-XDR-TB (i.e., TB that is resistant to isoniazid, rifampicin, plus any fluoroquinolones), and XDR-TB (i.e., TB that is resistant to isoniazid, rifampin, any fluoroquinolone, plus at least one additional drug categorized as a group A drug [levofloxacin/moxifloxacin, BDQ, or linezolid] OR a second-line injectable agent [amikacin, kanamycin, and capreomycin]) [14].Furthermore, data on safety and efficacy were extracted.
2.4.Quality Assessment.Two reviewers (IS and YS) independently assessed the quality of all included RCTs using the Jadad scale, which includes the following three domains: randomization (scored 0, 1, or 2 points), double-blinding (scored 0, 1, or 2 points), and adequate reporting of withdrawals and dropouts (scored 0 or 1 point) [15].The total possible score ranges from 0 to 5 points.High-quality RCTs were those with a total score of ≥ 3, whereas those with a score of < 3 were considered low-quality studies.

Outcome Measures.
Safety outcomes incorporated allcause mortality, nonserious adverse effects (AEs), and serious AEs (SAEs).Efficacy outcome measures included culture conversion rate at 8-12 and 24-26 weeks, treatment success (defined as the sum of both cured and treatment completed), and time to culture conversion (in days).The definition of each treatment outcome was in accordance with the 2013 WHO outcome definition for DR-TB, which was also consistent with the definitions in other published studies [10,12,13,16].
2.6.Statistical Analysis.Safety outcome measures (i.e., allcause mortality, AEs, and SAEs) were regarded as dichotomous variables and were reported as relative risk (RR) with a 95% confidence interval (CI).Similarly, both early culture conversion rates and treatment success were described as dichotomous variables and reported as RR with a 95% CI.

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Pulmonary Medicine On the other hand, time to sputum culture conversion was a continuous variable (in days) and was reported as a standardized mean difference (SMD).A random-effect model was used owing to a variety of population origins.Heterogeneity between studies was evaluated using I 2 statistics, with the I 2 values of < 25%, 25%-75%, and > 75% considered as low, moderate, and high degrees of heterogeneity, respectively.Publication bias was evaluated through a funnel plot and Egger's regression test.In addition, standard leave-one-out sensitivity analyses were conducted for both safety and efficacy outcomes to identify the studies that exerted the most significant influence on the pooled estimates.A p value of less than 0.05 was considered statistically significant.All statistical analyses were performed using both the IBM SPSS Statistics for Mac (Version 28.0,IBM Corp., Armonk, NY) and Stata (Stata Statistical Software: Version 17, College Station, TX: StataCorp LP).

Characteristics of Included Studies. The included RCTs
were published between 2012 and 2023.The total pooled sample size was 2520 participants, 55.8% of whom received BDQ-containing regimens (n = 1408).The ratio of men to women was approximately 1.3-1.0.The majority of RCTs were open-label trials (n = 9), and only two studies reported blinding [8,17].The dose of oral BDQ was generally consistent among the majority of trials, with an initial dose of 400 mg per day for the first 2 weeks followed by 200 mg for up to 22-26 weeks.Three RCTs extended the BDQcontaining regimen beyond 30 weeks [18][19][20].Furthermore, sputum culture follow-up was performed at different times, ranging from 2 to 120 weeks after the initiation of treatment, but the majority were performed between Weeks 24 and 26.The characteristics of the included RCTs are summarized in Table 1.
Among the participants, patients with RR-TB constituted the largest cohort (n = 1303), followed by MDR-TB (n = 1142).Pre-XDR-TB was reported in a smaller population from a single study (n = 27), and there were no docu-mented cases of XDR-TB in the included RCTs (Supporting Information: Appendix 1).

Culture Conversion Rates, Treatment Success, and
Time to Culture Conversion.The rate of sputum culture conversion at 8-12 and 24-26 weeks was analyzed in eight and 15 RCTs, respectively.At Weeks 8-12, there was a significant difference in the culture conversion rate between the two arms (RR 95%CI = 1 35 [1.10-1.65],p value < 0 001), favoring the BDQ arm (Figure 3(a)).Furthermore, as shown in Figure 3(b), the analysis at 24-26 weeks revealed a significant 25% increase in the probability of culture conversion in the BDQ arm compared to the controls (RR 95%CI = 1 [1.15-1.36],p value < 0 001).Both study endpoints demonstrated a moderate degree of heterogeneity across RCTs, with I 2 = 61 34% for the culture conversion rate at Weeks 8-12 and I 2 = 47 28% at Weeks 24-26.
Treatment success was evaluated in eight RCTs (Figure 3(c)) and showed a significant 30% increase in the rate of favorable outcomes compared to the control group (RR 95%CI = 1 30 [1.17-1.44],p value < 0 001).In addition, for time to culture, a pooled SMD from seven RCTs showed approximately 17 fewer days to culture conversion compared to the controls (SMD 95%CI = −17 46 [−34.82 to −0.11], p value = 0 05) (Figure 3(d)).The heterogeneity of the treatment success outcome across studies was low (I 2 = 28 08%), whereas between-study heterogeneity for time to culture conversion was high (I 2 = 99 37%).Pulmonary Medicine 3.5.Publication Bias Assessment.The funnel plots of all study endpoints are shown in Supporting Information: Appendix 4. For the safety outcomes, a regression-based Egger's test for small-study effects demonstrated a low risk of publication bias for all-cause mortality (p value = 0 98) and SAEs (p value = 0 16), whereas AEs demonstrated a high risk of publication bias (p value < 0 001).On the other hand, efficacy endpoints invariably demonstrated a high-risk publication bias in culture conversion at 8-12 weeks (p value < 0 001) and 24-26 weeks (p value < 0 001) and in time to culture conversion (p value < 0 001).The treatment success endpoints demonstrated a low-risk publication bias (p value = 0 07).

Discussion
The treatment strategy for DR-TB has evolved throughout the decades [33].Most recently, the 2019 WHO Consolidated Guidelines on Drug-Resistant TB reclassified antituberculosis agents into groups A, B, and C; BDQ was incorporated into group A along with linezolid and moxifloxacin/levofloxacin [34].As treatment with group A drugs should be prioritized whenever possible, BDQ has become one of the most important regimens to combat DR-TB infections.This systematic review and meta-analysis assessed 18 RCTs to evaluate the safety and efficacy of BDQ-containing regimens in the treatment of DR-TB.Overall, the findings suggest no difference in all-cause mortality or SAEs; AEs were significantly higher in the BDQreceiving arm.Furthermore, BDQ-containing regimens significantly improved both early (8-12 weeks) and late (24-26 weeks) culture conversion rates and treatment success, and the time to culture conversion was accelerated by 17 days.This is the first study that has attempted to evaluate pooled evidence of the safety and efficacy of BDQ in the treatment of DR-TB based exclusively on available data from RCTs.Our findings suggest an insignificant mortality benefit of BDQ-containing regimens.At the time of writing this meta-analysis, two published meta-analyses have examined pooled evidence on mortality based on mostly observational

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Pulmonary Medicine      7 Pulmonary Medicine studies, both of which contradicted our finding [10,11].A review by Wang, Wu, and He [10] involving eight studies, two of which were RCTs, demonstrated a significant 47% reduction in mortality risk in the BDQ-treatment arm.Their finding was consistent with a review by Rehman et al. [13] and a subgroup analysis of pooled observational studies by Tong et al. [11], which demonstrated a significant mortality risk reduction of 27% and 32%, respectively.In contrast, the pooled analysis of five RCTs by Tong et al. [11] demonstrated a nonsignificant increase in mortality.This discrepancy and inconsistency in mortality benefit findings may be attributed to the inclusion of discrete categories of studies in each review.However, it is evident that the inclusion of more RCTs in our study has resulted in an insignificant reduction in mortality.
All 18 included RCTs reported data on AEs, whereas only 17 trials reported on SAEs.Importantly, patients treated with BDQ exhibited a significant 28% higher risk of nonserious AEs compared to the control group.However, most AEs are considered mild to moderate and do not necessitate the discontinuation of BDQ-containing regimens [35].Other drugs in DR-TB regimens, however, may contribute to various accompanying AEs [17,19].Unlike the finding of a significantly higher risk of AEs in the BDQ arm, our study found a nonsignificant difference in SAEs between the two arms.This is in contrast to the review by Tong et al. that reported a significant 42% higher probability of Grade 3-5 AEs in the BDQ group compared to the control group [11].This discrepancy might be due to variations in sample characteristics; Tong et al. [11] included mostly observational studies.In addition, there may have been differences in how AEs were classified and defined by the individual studies.
Our analysis revealed significantly higher culture conversion rates with BDQ-containing regimens at both 8-12 weeks and 24-26 weeks by 35% and 25%, respectively.This is consistent with other studies by Wang, Wu, and He [10] and Tong et al. [11], who also noted improvement in the overall culture conversion rate.Moreover, the RCT subanalysis by Tong et al. [11] of the culture conversion rate at 24 weeks was 27% higher among the BDQ-regimen group.We also found that the treatment success rate was significantly higher by 30% among the BDQ-containing regimen arm.Apart from Wang, Wu, and He [10], all previous systematic reviews [11][12][13] reported significant improvement in the treatment success rate.
The current conditional recommendation in the updated 2022 WHO Consolidated Guidelines on Tuberculosis suggests a 6-month treatment with a combination of BDQ,       9 Pulmonary Medicine pretomanid, linezolid (600 mg), and moxifloxacin, known as the BpaLM regimen, for RR-TB, MDR-TB, and pre-XDR-TB (quality of evidence: very low) [36].This is shorter than the previously recommended 9 months or longer duration [34,36].The guidelines suggest that the initiation should not be delayed by the drug susceptibility testing (DST) for fluoroquinolones.The moxifloxacin, however, should be stopped if fluoroquinolone resistance is proven by a DST (i.e., use a BPaL regimen instead of a BpaLM regimen).Available data from the 2-stage phase 2/3 TB-PRACTECAL trial showed higher treatment success rates with BPaLM compared to standard of care regimens (89% vs. 52% among patients with RR-TB) [25].The BPaLM regimen also had superior treatment success compared to BPaL and BPaLC (i.e., BPaL plus clofazimine) regimens (89% vs. 81% and 77%, respectively) [25].
Apart from the published TB-PRACTECAL, ZeNIX, and NIX-TB trials that incorporated BDQ (especially in the BPaL or BpaLM formulation regimens) [25,37,38], several other clinical trials are also ongoing.These include the following from clinicaltrials.govregistries: • NCT06058299: Phase 2 trial assessing TBAJ876 or BDQ, with pretomanid and linezolid in adults with drug-sensitive pulmonary tuberculosis These pursuits toward establishing the risks and benefits of these combination drugs are a positive trend that will advance the use of BDQ and help fight against DR-TB for decades to come.
4.1.Strengths and Limitations.Our meta-analysis consisted exclusively of prospective clinical trials with the appropriate controlled arms, and during the Jadad score assessment, we eliminated any study that did not apply a randomization strategy.We also incorporated an additional Chinese database, that is, SinoMed, into our search strategy, which resulted in the inclusion of 11 more RCTs (61% of total included RCTs).This eliminated the language barrier limitation and considerably improved the pooled analysis in our study.We performed analyses on early culture conversion (Weeks 8-12) and culture conversion after the BDQ intensive phase ended (Weeks 24-26).The findings in our study clearly point toward the superiority of combining BDQ with other second-line agents.
However, this study had several limitations.The limited data on each resistance profile in the individual RCTs, that is, RR-TB, MDR-TB, pre-XDR-TB, and XDR-TB, limited the subgroup analyses for both the safety and efficacy outcomes.There was also insufficient data on pregnant women, children, and individuals with human immunodeficiency virus (HIV) infection and with chronic liver, cardiac, and renal comorbidities.Furthermore, the lack of blinding in the majority of the BDQ RCTs and its effect on the studies' quality may also have affected the reliability of the pooled estimates in this review.Finally, the analyses on AEs and SAEs did not specify which organ systems were affected.Not enough is known about BDQ's cardiotoxic side effects, particularly its proarrhythmogenic potential to widen the QT interval.Future studies should explore pooled data from clinical trials on arrhythmogenic side effects of BDQ.

Conclusion
This review provides strong evidence for the efficacy and safety of BDQ-containing regimens in the treatment of DR-TB.Patients receiving BDQ had significantly higher rates of treatment success and culture conversion both at Weeks 8-12 and Weeks 24-26 compared to BDQ-free patients.This suggests better success in the eradication of TB infections.Although some AEs were more common with BDQ, they were not significantly more severe.However, limitations like limited data on specific resistance profiles and the potential for proarrhythmogenic effects highlight the need for further studies.Overall, this study strengthens the evidence for administering BDQ in the fight against DR-TB.

Figure 2 :
Figure 2: Forest plot of safety outcomes, including (a) all-cause mortality, (b) serious adverse events, and (c) adverse events.

Figure 3 :
Figure 3: Forest plot of efficacy outcomes, including sputum culture conversion rate at (a) 8-12 weeks and at (b) 24-26 weeks, (c) treatment success, and (d) time to culture conversion (days).SMD, standardized mean difference.

Table 1 :
Baseline characteristics of the included RCTs.